Epidemiologic studies have shown that the incidence of pancreatic cancer is greater in countries that consume diets high in fat. Furthermore, obesity has been reported as a risk factor for the development of pancreatic cancer. Many factors have been associated with the relationship of diet or obesity and pancreatic cancer including leptin, glucose dysregulation, insulin growth factor (IGF), and inflammation. This project is unique in that we aim to show that dietary fat promotes growth of pancreatic cancer by the actions of the gastrointestinal trophic peptide cholecystokinin (CCK) on its receptor. Under physiologic conditions, CCK is released in response to dietary fat in order to stimulate secretion of pancreatic digestive enzymes, regulate insulin, and contract the gall bladder through the CCK receptor. We have demonstrated the presence of CCK receptors on early precancerous pancreatic epithelial neoplasias (PanINs) and CCK receptor blockade completely halts progression of these precursor lesions to form cancer in a transgenic KRAS murine model. CCK receptors are also abundantly over-expressed in cancer where they are involved in stimulating growth. Obese animals have been shown to have 500-fold greater CCK levels and also an enhanced growth rate of xenografted pancreatic cancer. We have also shown that mice bearing either subcutaneous or orthotopic pancreatic cancers, had significantly larger tumors and more metastases when fed a diet high in fat compared to mice on a low fat or normal diet. This growth stimulatory effect of pancreatic cancer by a high fat diet was blocked with concomitant administration of a CCK receptor antagonist suggesting the CCK: CCK-receptor pathway as an important, if not the key factor, in dietary-fat associated pancreatic cancer. It is hypothesized that dietary fat stimulates CCK release which promotes growth of pancreatic cancer through its mitogenic actions on the CCK receptor. In order to test this hypothesis we will perform the following specific aims: 1) Examine the role of the CCK: CCK-receptor axis on growth and metastasis of an orthotopically transplanted pancreatic cancer in a syngeneic (species specific) immunocompetent murine model by pharmacologic blockade, and 2) Examine the role of the CCK: CCK-receptor axis on growth and metastasis of pancreatic cancer in genetically engineered models that either lack the CCK receptor or the CCK peptide. Since CCK receptor antagonists are available and have oral bioavailability, results of this project may be readily translated to the clinic. These investigations if successful will facilitate in our understanding o the risks that lead to pancreatic cancer and will provide potential novel therapies to inhibit or prevent growth and metastases in patients with pancreatic cancer.